Identification of the protein disulfide isomerase family member PDIp in experimental Parkinson's disease and Lewy body pathology

Conn, Kelly J.; Gao, Wenwu; McKee, Ann C.; Lan, Michael S.; Ullman, M. David; Eisenhauer, Patricia B.; Fine, Richard E.; Wells, John M.

doi:10.1016/j.brainres.2004.07.026

Cited by 135 publications

(93 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Co-expression of PDI with synphilin-1 in cultured SH-SY5Y cells greatly decreased discrete Lewy-body-like inclusions formed by synphilin-1 in the cytoplasm; and Snitrosylation of PDI by nitric oxide attenuated this inhibiting effect (Uehara et al 2006). Moreover, by means of immunohistochemistry, pancreatic PDI was shown to colocalize with αSyn in Lewy bodies in the postmortem human brain tissue from patients with Dementia with Lewy bodies (Conn et al 2004). Hence, PDI may function in the cytoplasm to play protective roles against αSyn cytotoxicity.…”

Section: Discussionmentioning

confidence: 95%

Domain a’ of protein disulfide isomerase plays key role in inhibiting α-synuclein fibril formation

Cheng

Wang

2010

Cell Stress and Chaperones

View full text Add to dashboard Cite

α-Synuclein (αSyn) is the main component of Lewy bodies formed in midbrain dopaminergic neurons which is a pathological characteristic of Parkinson's disease. It has been recently showed to induce endoplasmic reticulum (ER) stress and impair ER functions. However, the mechanism of how ER responds to αSyn toxicity is poorly understood. In the present study, we found that protein disulfide isomerase (PDI), a stress protein abundant in ER, effectively inhibits αSyn fibril formation in vitro. In PDI molecule with a structure of abb'xa'c, domain a' was found to be essential and sufficient for PDI to inhibit αSyn fibril formation. PDI was further found to be more avid for binding with intermediate species formed during αSyn fibril formation, and the binding was more intensive in the later lag phase. Our results provide new insight into the role of PDI in protecting ER from the deleterious effects of misfolded protein accumulation in many neurodegenerative diseases.

show abstract

Section: Discussionmentioning

confidence: 95%

Domain a’ of protein disulfide isomerase plays key role in inhibiting α-synuclein fibril formation

Cheng

Wang

2010

Cell Stress and Chaperones

View full text Add to dashboard Cite

show abstract

“…82 Accumulation of immature and denatured proteins results in ER dysfunction in brains of AD, PD, ALS, prion disease, cerebral ischemia, and possibly other neurodegenerative disorders, but upregulation of PDI represents an adaptive response promoting protein refolding and may offer neuronal cell protection. [83][84][85][86][87][88][89][90] Recently, we reported that excessive NO can lead to S-nitrosylation of the active site thiol groups of PDI, and Figure 3 Possible mechanism of S-nitrosylated PDI (SNO-PDI) contributing to the accumulation of aberrant proteins and neuronal cell damage or death. ER stress is triggered when misfolded proteins accumulate within the ER lumen, inducing the UPR.…”

Section: S-nitrosylation As a Potential Positive Regulator Of Excitotmentioning

confidence: 99%

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

Nakamura

Lipton

2007

Cell Death Differ

View full text Add to dashboard Cite

Although activation of glutamate receptors is essential for normal brain function, excessive activity leads to a form of neurotoxicity known as excitotoxicity. Key mediators of excitotoxic damage include overactivation of N-methyl-D-aspartate (NMDA) receptors, resulting in excessive Ca 2 þ influx with production of free radicals and other injurious pathways. Overproduction of free radical nitric oxide (NO) contributes to acute and chronic neurodegenerative disorders. NO can react with cysteine thiol groups to form S-nitrosothiols and thus change protein function. S-nitrosylation can result in neuroprotective or neurodestructive consequences depending on the protein involved. Many neurodegenerative diseases manifest conformational changes in proteins that result in misfolding and aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Molecular chaperones -such as protein-disulfide isomerase, glucose-regulated protein 78, and heat-shock proteins -can provide neuroprotection by facilitating proper protein folding. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence that NO contributes to degenerative conditions by S-nitrosylating-specific chaperones that would otherwise prevent accumulation of misfolded proteins and neuronal cell death. In contrast, we also review therapeutics that can abrogate excitotoxic damage by preventing excessive NMDA receptor activity, in part via S-nitrosylation of this receptor to curtail excessive activity.

show abstract

“…Increased phosphorylation of PERK and eIF2α was in co-localization with α-synuclein inclusions was reported in the substancia nigra of PD patients. Other studies were also able to identify other ER stress markers in brain tissue from PD patients such as PDI [66] and components of ERAD like Herp [67] in co-localization with Lewy bodies and recently tunicamycin was shown to induce α-synuclein oligomerization in vivo [68].…”

Section: Parkinson's Diseasementioning

confidence: 99%

ER stress in neurodegenerative disease: from disease mechanisms to therapeutic interventions

Cabral‐Miranda

Hetz

2017

Endoplasmic Reticulum Stress in Diseases

View full text Add to dashboard Cite

The conception that protein aggregates composed by misfolded proteins underlies the occurrence of several neurodegenerative diseases suggests that this phenomenon may have a common origin, ultimately driven by disruption of proteostasis control. The unfolded protein response (UPR) embodies a major element of the proteostasis network, which is engaged by endoplasmic reticulum (ER) stress. Chronic ER stress may operate as a possible mechanism of neurodegeneration, contributing to synaptic alterations, neuroinflammation and neuronal loss. In this review we discuss most recent findings relating ER stress and the development of distinct neurodegenerative diseases, and the possible strategies for disease intervention.

show abstract

Identification of the protein disulfide isomerase family member PDIp in experimental Parkinson's disease and Lewy body pathology

Cited by 135 publications

References 36 publications

Domain a’ of protein disulfide isomerase plays key role in inhibiting α-synuclein fibril formation

Domain a’ of protein disulfide isomerase plays key role in inhibiting α-synuclein fibril formation

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

ER stress in neurodegenerative disease: from disease mechanisms to therapeutic interventions

Contact Info

Product

Resources

About